Читать книгу Inferior: How Science Got Women Wrong – and the New Research That’s Rewriting The Story - Angela Saini, Angela Saini - Страница 10

The evidence is clear: from the constitutional standpoint woman is the stronger sex.

Ashley Montagu, The Natural Superiority of Women (1953)

‘It’s wonderful,’ says Mitu Khurana, a hospital administrator living in New Delhi. ‘When you have your first pregnancy, everyone is very excited. It is a feeling beyond description.’

The time she’s so fondly remembering was a decade ago. She had become pregnant with twins just a few months after getting married, and she assumed that nothing could ruin her happiness. Raised in a family of sisters, Mitu didn’t care whether she was having boys or girls, or one of each. ‘I just wanted the children to be healthy,’ she tells me.

But her husband and his family didn’t feel the same way. They wanted sons.

So begins a common story. It’s one that has been repeated in millions of homes across India, China and other parts of South Asia, where cultures unashamedly prize sons above daughters. They are cultures, as Mitu learned all those years ago, that will sometimes go to terrible lengths to stop a girl from even being born. Some women keep having children until they finally have a boy. Others are pressured to abort female foetuses, even to the point of torture. If they do make it to the day of their birth, many female babies and young girls are routinely treated worse than boys. In the most appalling cases, they are killed. In 2007, police in Orissa in the east of India found skulls and body parts of what they believed to be three dozen female foetuses and infants down a disused well. A news report in 2013 described a baby buried alive in a forest in the central state of Madhya Pradesh. Another in 2014 told of a newborn in Bhopal dumped in a rubbish bin.

That year, a United Nations report described the problem as having reached emergency levels. India’s 2011 census had already revealed that there were more than seven million fewer girls than boys aged six and under. The overall sex ratio was more skewed in favour of boys than it had been a decade ago. Part of the reason was the growing availability of prenatal scans, which for the first time allowed parents to find out the sex of their babies easily, and early enough to have selective abortions.

In 1994 the Indian government outlawed sex selection tests, but unscrupulous independent clinics and doctors still offer them for a fee, in private and under the radar. Mitu never wanted to have one of these prenatal scans, she tells me. But in the end, she wasn’t given the choice. During her pregnancy, she claims she was tricked into eating some cake that contained egg, to which she is allergic. Her husband, a doctor, then took her to a hospital, where a gynaecologist advised her to have a kidney scan under sedation. It was then, she believes, that her husband found out the sex of her unborn babies without her consent or knowledge.

‘I knew it from his behaviour that I’m getting daughters,’ she explains. He and his family immediately began pressing her to have an abortion. ‘There was a lot of pressure.’ She says she was denied food and water, and was once pushed down the stairs. Desperate and frightened, Mitu went to stay with her parents, and eventually gave birth to her daughters there.

She managed to save her girls. But things didn’t change. ‘They were not at all warm,’ she recalls of her husband and his family’s attitude towards her daughters. A few years later she stumbled on an old hospital report revealing the sex of her foetuses. She read it as proof that her husband had indeed carried out an ultrasound scan on her while she was pregnant, without her consent. As a result of that discovery she launched a legal case against both him and the hospital, which is still making its way through the notoriously slow Indian courts at the time I interview her, ten years after the birth of her daughters. Her husband and the hospital have both strongly denied her allegations.

Now long-separated from her husband and awaiting a divorce, Mitu has become famous in India for being among the first women to take this kind of legal action. Taking her campaign across the country has confirmed to her just how widespread a problem this is, blind to class or religion. ‘I’m fighting because I don’t want my daughters to go through this. Women are wanted as wives and girlfriends, but not as daughters,’ she says. ‘Society has to change.’

However well-hidden the selective abortions, murders and abuse of mothers and their daughters, the countrywide statistics don’t lie. Reality is laid bare in the grotesquely uneven sex ratios. The 2015 United Nations report The World’s Women says, ‘For those countries in which the sex ratio falls close to or below the parity line, it can be assumed that discrimination against girls exists.’

It is a situation familiar to Joy Lawn, director of the Centre for Maternal, Adolescent, Reproductive and Child Health at the London School of Hygiene and Tropical Medicine. ‘You go to hospitals in South Asia and there can be whole wards of kids with illnesses, and you will find 80 per cent of them are boys, because the girls aren’t being brought to the hospital,’ she tells me. A similar gender imbalance was uncovered in a 2002 study in Nepal by public health researchers Miki Yamanaka and Ann Ashworth, also from the London School of Hygiene and Tropical Medicine. They looked at how much work children are expected to do to support their families, and found that girls worked twice as long as boys, and that their work was also heavier.

The effects that society can have on gender differences are profound, and include the taking of life itself. What makes the mortality figures even more shocking is that, contrary to assumptions about women being the weaker sex, a baby girl is statistically more robust than a baby boy. She’s naturally better built to live. As scientists explore the female body in fuller detail, they are learning just how powerful a girl’s survival edge is – even in a world that doesn’t always want her.

‘Pretty much at every age, women seem to survive better than men.’

We often think of males as being the tougher and more powerful sex. It’s true that men are on average six inches taller and have around double the upper-body strength of women. But then, strength can be defined in different ways. When it comes to the most basic instinct of all – survival – women’s bodies tend to be better equipped than men’s.

The difference is there from the very moment a child is born.

‘When we were there on the neonatal unit and a boy came out, you were taught that, statistically, the boy is more likely to die,’ explains Joy Lawn. Besides her academic research into child health, she has worked in neonatal medicine in the United Kingdom and as a paediatrician in Ghana. The first month following birth is the time at which humans are at their greatest risk of death. Worldwide, a million babies die on the day of their birth every year. But if they receive exactly the same level of care, females are statistically less likely to die than males. Lawn’s research encompasses data from across the globe, giving the broadest picture possible of infant mortality. And having researched the issue in such depth, she concludes that boys are at around a 10 per cent greater risk than girls in that first month – and this is at least partly, if not wholly, for biological reasons.

Thus, in South Asia, as elsewhere in the world, the mortality figures should be in favour of girls. The fact that they’re not even equal, but are skewed in favour of boys, means that girls’ natural power to survive is being forcibly degraded by the societies they are born into. ‘If you have parity in your survival rates, it means you aren’t looking after girls,’ says Lawn. ‘The biological risk is against the boy, but the social risk is against the girl.’

Elsewhere, child mortality statistics bear this out. For every thousand live births in sub-Saharan Africa, ninety-eight boys compared with eighty-six girls die by the age of five. Research Lawn and her colleagues published in the journal Pediatric Research in 2013 confirmed that a boy is 14 per cent more likely to be born prematurely than a girl, and is more likely to suffer disabilities ranging from blindness and deafness to cerebral palsy when he’s at the same stage of prematurity as a girl. In the same journal in 2012 a team from King’s College London reported that male babies born very prematurely are more likely to stay longer in hospital, to die, or to suffer brain and breathing problems.

‘I always thought that it was physically mediated, because boys are slightly bigger, but I think it’s also biological susceptibility to injury,’ says Lawn. One explanation for more boys being born preterm is that mothers expecting boys are, for reasons unknown, more likely to have placental problems and high blood pressure. Research published by scientists from the University of Adelaide in the journal Molecular Human Reproduction in 2014 showed that newborn girls may be healthier on average because a mother’s placenta behaves differently depending on the sex of the baby. With female foetuses, the placenta does more to maintain the pregnancy and increase immunity against infections. Why this is, nobody understands. It could be because, before birth, the normal human sex ratio is slightly skewed towards boys. The difference after birth might simply be nature’s way of correcting the balance.

But the reasons could also be more complicated. After all, a baby girl’s natural survival edge stays with her throughout her entire life. Girls aren’t just born survivors, they grow up to be better survivors too.

‘Pretty much at every age, women seem to survive better than men,’ confirms Steven Austad, chair of the biology department at the University of Alabama at Birmingham, who is an international expert on ageing. He describes women as being more ‘robust’. It’s a phenomenon so clear and undeniable that some scientists believe understanding it may hold the key to human longevity.

At the turn of the millennium, Austad began to investigate exactly what it is that helps women outlive men at all stages of life. ‘I wondered if this is a recent phenomenon. Is this something that’s only true in industrialised countries in the twentieth century and twenty-first century?’ Digging through the Human Mortality Database, a collection of longevity records from around the world founded by German and American researchers in 2000, he was surprised to discover that the phenomenon really does transcend time and place.

The database now covers thirty-eight countries and regions. Austad’s favourite example is Sweden, which has kept some of the most thorough and reliable demographic data of any country. In 1800 life expectancy at birth in Sweden stood at thirty-three years for women and thirty-one for men. In 2015 it was around eighty-three for women and around seventy-nine for men. ‘Women are more robust than men. I think there’s little doubt about that,’ Austad says. ‘It was true in the eighteenth century in Sweden, and it’s true in the twenty-first century in Bangladesh, and in Europe, and in the US.’

I ask Austad whether women might be naturally outliving men for social reasons. It’s reasonable to think, for instance, that boys are generally handled more roughly than girls are. Or that more men than women take on risky jobs, such as construction and mining, which also expose them to toxic environments. And we know that in total across the world, far more men than women smoke, which dramatically pushes up mortality rates. But Austad is convinced that the difference is so pronounced, ubiquitous and timeless that it must mean there are features in a woman’s body that underlie the difference. ‘It’s hard for me to imagine that it is environmental, to tell you the truth,’ he says.

The picture of this survival advantage is starkest at the end of life. The Gerontology Research Group in the United States keeps a list online of all the people in the world that it has confirmed are living past the age of 110. I last checked the site in July 2016. Of all these ‘supercentenarians’ in their catalogue, just two were men. Forty-six were women.

Yet we don’t know why.

‘I’m absolutely puzzled by it,’ says Austad. ‘When I first started looking into this, I expected to find a huge literature on it, and I found virtually nothing. There’s a big literature on “Is this a difference between men and women?”, but the underlying biology of the survival difference, there’s very little on that. It’s one of the most robust features of human biology that we know about, and yet it’s had so little investigation.’

For more than a century, scientists have painstakingly studied our anatomy, even collected thousands of litres of horse urine in their attempts to isolate the chemicals that make men more masculine and women more feminine. Their search for sex differences has had no boundaries. But when it comes to why women might be more physically robust than men – why they are better survivors – research has been scarce. Even now, only scraps of work here and there point to answers.

‘It’s a basic fact of biology,’ observes Kathryn Sandberg, director of the Center for the Study of Sex Differences in Health, Aging and Disease at Georgetown University in Washington, DC, who has explored how much of a role disease has to play in why women survive. ‘Women live about five or six years longer than men across almost every society, and that’s been true for centuries. First of all, you have differences in the age of onset of disease. So, for example, cardiovascular disease occurs much earlier in men than women. The age of onset of hypertension, which is high blood pressure, also occurs much earlier in men than women. There’s also a sex difference in the rate of progression of disease. If you take chronic kidney disease, the rate of progression is more rapid in men than in women.’ Even in laboratory studies on animals, including mice and dogs, females have done better than males, she adds.

By picking through the data, researchers like her, Joy Lawn and Steven Austad have come to understand just how widespread these gaps are. ‘I assumed that these sex differences were just a product of modern Westernised society, or largely driven by the differences in cardiovascular diseases,’ says Austad. ‘Once I started investigating, I found that women had resistance to almost all the major causes of death.’ One of his papers shows that in the United States in 2010, women died at lower rates than men from twelve of the fifteen most common causes of death, including cancer and heart disease, when adjusted for age. Of the three exceptions, their likelihood of dying from Parkinson’s or stroke was about the same. And they were more likely than men to die of Alzheimer’s Disease.

When it comes to fighting off infections from viruses and bacteria, women also seem to be tougher. ‘If there’s a really bad infection, they survive better. If it’s about the duration of the infection, women will respond faster, and the infection will be over faster in women than in men,’ says Kathryn Sandberg. ‘If you look across all the different types of infections, women have a more robust immune response.’ It isn’t that women don’t get sick. They do. They just don’t die from these sicknesses as easily or as quickly as men do.

One explanation for this gap is that higher levels of oestrogen and progesterone in women might be protecting them in some way. These hormones don’t just make the immune system stronger, but also more flexible, according to Sabine Oertelt-Prigione, a researcher at the Institute of Gender in Medicine at the Charité University Hospital in Berlin. ‘This is related to the fact that women can bear children,’ she explains. A pregnancy is the same as foreign tissue growing inside a woman’s body that, if her immune system was in the wrong gear, would be rejected. ‘You need an immune system that’s able to switch from pro-inflammatory reactions to anti-inflammatory reactions in order to avoid having an abortion pretty much every time you get pregnant. The immune system needs to have mechanisms that can, on one side, trigger all these cells to come together in one spot and attack whatever agent is making you sick. But then you also need to be able to stop this response when the agent is not there any more, in order to prevent tissues and organs from being harmed.’

The hormonal changes that affect a woman’s immune system during pregnancy also take place on a smaller scale during her menstrual cycle, and for the same reasons. ‘Women have more plastic immune systems. They adapt in different ways,’ says Oertelt-Prigione. Many types of cell in the body are involved in immunity, but the kind that come into closest contact with viruses and bacteria are known as T cells. They inject substances into bacteria to kill them, or secrete other substances that call more cells to action, some of which ‘eat up’ infected cells and bacteria, like Pac-Man in the video game, she explains. Researchers know that a certain type of T cell that’s crucial to managing the body’s response to infections becomes more active in the second half of a woman’s menstrual cycle, when she’s able to get pregnant.

The discovery that sex hormones and immunity might be linked is fairly recent. In men, scientists have explored connections between testosterone and lower immunity, although the evidence is relatively thin. In 2014, for example, Stanford University researchers found that males with the highest levels of testosterone had the lowest antibody response to a flu vaccine, which meant they were the least likely to be protected by the jab. As yet, though, it’s an unsubstantiated link. In women, the connection is far clearer. So much so that patients themselves have noticed these fluctuations. For years, doctors assumed that a woman’s immunity didn’t change during her menstrual cycle. If she did report a difference in pain levels, doctors might dismiss it as premenstrual syndrome, or some vague psychological complaint. It was only when these links were increasingly backed up by hard research that scientific interest was sparked, and more research began to flourish.

This problem runs all the way through research into women’s health. If a phenomenon affects women, and only women, it’s all too often misunderstood. And this is compounded by the fact that even though they’re better at surviving, women aren’t healthier than men. In fact, quite the opposite.

‘If you could add up all the pain in the world, all the physical pain, I suspect that women have way, way more of it. This is one of the penalties of being a better survivor. You survive, but maybe not quite as intact as you were before,’ says Steven Austad. Statistically, this could explain why women seem proportionally sicker than men. ‘Part of the reason that there are more women than men around in ill health is to do with the fact that women have survived events that would kill men, and so the equivalent men are no longer with us.’

Another reason is that women’s immune systems are so powerful that they can sometimes backfire. ‘You start regarding yourself as foreign, and your immune system starts attacking its own cells,’ explains Kathryn Sandberg. Diseases caused in this way are known as autoimmune disorders. The most common include rheumatoid arthritis, lupus and multiple sclerosis. ‘It’s kind of a double-edged sword with the immune system. In some ways it’s better to have a female immune system if you’re fighting off infection of any kind, but on the other hand, we are more susceptible to autoimmune diseases, which are very problematic.’

This isn’t to say that autoimmune disease is always hardest on women. When men get multiple sclerosis, they tend to get it worse. Women also survive with it longer than men do. Even so, of the roughly 8 per cent of Americans who suffer from auto-immune diseases, estimates suggest that at least three-quarters are women.

‘In autoimmune diseases, they almost all tend to get worse right before the menstrual cycle in women who are premenopausal,’ says Sabine Oertelt-Prigione. In the same way that varying hormone levels may boost a woman’s immunity at different times of the month, there are theories that they might also affect her experience of illness. There are reports, for instance, that women with asthma are at highest risk of an attack just before or at the start of their period. As oestrogen and progesterone levels drop in the years following the start of the menopause, a woman’s immunity advantage starts to drop away as well.

When it comes to viral infections, too, a woman’s strong immune response may be a problem as well as a benefit. Research on influenza by Sabra Klein, an immunologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, has shown that while women are generally hit by fewer viruses during an infection, they tend to suffer more severe flu symptoms than men do. She reasons that this may be because women’s immune systems mount sturdier counter-attacks against viruses, but then suffer when the effects of these counter-attacks impact their own bodies.

Women also tend to get more painful joint and muscle diseases, observes Steven Austad. Part of this is down to autoimmune diseases that affect the joints, such as arthritis. The physical toll of childbearing and the hormonal changes of menopause may also leave women with physical problems and disabilities, especially in later life. Bone density is known to fall short-term after pregnancy, and after the menopause. Weight gain is now also recognised as a symptom of menopause.

But the overall picture of pain and ill-health is complicated. ‘Cross-culturally, women just report more physical limitations and more disabilities. It’s really widespread,’ says Austad. When it comes to biological clues about the underlying reasons for this sex difference in disease or survival, however, he adds, ‘I don’t feel very confident of any explanation.’

It’s difficult to tear apart biology from other effects. Society and the environment can sometimes impact illness more than a person’s underlying biology. ‘Women are less likely to go to the hospital when they’re feeling chest pain than men,’ says Kathryn Sandberg, who has looked at gender differences in heart disease in particular. There are countless other ways in which men’s and women’s health habits differ throughout the world. Sabine Oertelt-Prigione points out that where families eat collectively and food is scarce, women are sometimes the last to eat and are the most likely to go without food, which can raise their risk of malnutrition. This in turn can affect their susceptibility to disease.

Not only a woman’s own behaviour, but that of others around her, can affect her health. From the second a girl is born, she’s placed in a different box from a boy. She may be handled differently, fed differently and treated differently. And this marks the beginning of a lifetime of differences in the way doctors and medical researchers approach her as well. Only very recently, for instance, have doctors begun to acknowledge the severity of some women’s experience of period pain. In 2016, professor of reproductive health at University College London, John Guillebaud, told a reporter that period pain can be ‘almost as bad as having a heart attack’, and admitted that it hasn’t been given the attention it deserves, partly because men don’t suffer from it. In 2015, a team of British researchers studying cancer diagnosis in the UK found that it took longer for women to be diagnosed after going to a doctor in six of the cancers that affect both men and women, including bladder and lung. For gastric cancer, a woman waited on average a full two weeks longer for a diagnosis.

If there are underlying biological sex differences in health, and the differences aren’t largely down to society and culture, then scientists need to go deeper inside the body to find them.

‘Females get sicker but males die quicker,’ says Arthur Arnold, a professor at the University of California, Los Angeles. It’s an old adage, bandied among his undergraduates. It reflects what doctors all over the world have observed, and Arnold is convinced that it reveals the long roots of sex differences in health. He runs a laboratory studying the biological factors that make females different from males, and edits the journal Biology of Sex Differences. His work has taken him beyond looking at organs and sex hormones, and down to the fundamental level of the gene.

The human body is made up of trillions of cells. Every one of them has genetic information stored in packages known as chromosomes, explaining to our bodies how to build themselves up from the subtlest hormones all the way up to skin and bone. We have forty-six chromosomes in total, split into twenty-three pairs, and the roots of the genetic differences between men and women lie in our twenty-third pair, known as the sex chromosomes. In women, they’re called XX, with one X chromosome inherited from each parent. Men’s sex chromosomes are called XY, with the X coming from the mother and the Y from the father. For a long time it was assumed that these sex chromosomes were mainly concerned with reproduction and not much else. Today some scientists, including Arnold, believe that the consequences of this seemingly tiny genetic difference may stretch much further.

Every chromosome in a pair carries the same genes in the same locations, known as alleles. The one for eye colour from a person’s father, for example, will be matched by another one for eye colour in the same place from the mother. That’s true of a female’s two X chromosomes too. For males with XY sex chromosomes, however, a matching allele isn’t always there. X and Y don’t have the same genes in the same locations. In fact, the Y is far smaller than the X.

Having just one copy of the genes on the X chromosome can have repercussions for a man’s body. ‘It’s long been thought, and there is good evidence for this, that having two versions of the gene buffers women against certain diseases or environmental changes,’ says Arnold. If a man happens to have a genetic mutation on one of his X chromosomes that causes an illness or disability, he has no way of avoiding it. A woman, on the other hand, will have an extra X chromosome to counteract it, unless she’s unlucky enough to have the same genetic mutation on both of her X chromosomes, one from each parent. ‘The simple case would be if one gene works better when it’s cold and another works better when it’s hot. A woman with both of those alleles can be healthy when it’s hot and cold. The male only gets one shot. He only has one copy. So his body either works better when it’s hot or works better when it’s cold, but not both.’

There are some well-known genetic traits to which men are more susceptible than women simply because they have one X chromosome. These X-linked disorders include red-green colour blindness, haemophilia, muscular dystrophy and IPEX syndrome, which affects immune function. Mental retardation, which affects 2 to 3 per cent of people in developed countries, and significantly more men than women, also has a strong link to the X chromosome.

This is a reason why, in the effort to understand sex differences in health, Arthur Arnold has chosen to zero in on chromosomes. ‘We went back to the most fundamental biological differences between males and females. From the time of the fertilisation of the egg, the only one thing that we know is different between males and females is sex chromosomes. So everything has got to come from that … everything’s downstream of the sex chromosomes.’

‘What we know of X-linked diseases is that they’re pretty rare,’ says Steven Austad. ‘But I think there are a lot more X-linked diseases than we think about. I think this probably underlies a considerable proportion of the sex difference.’ One example is respiratory syncytial virus, which infects the lungs and breathing passages and is one of the biggest causes of bronchitis in children under the age of one in Britain and the United States. Researchers have found that the virus tends to hit boys far more than girls, and that something inside one particular gene on the X chromosome might be responsible.

Sabine Oertelt-Prigione agrees that there may be genes linked to resilience, immunity and disease susceptibility on the human X chromosome that haven’t yet been discovered or understood. ‘In my school we were taught that the X and Y are basically related to sexual function. That’s it. Nobody was thinking beyond that really at the time, and I’m talking about twenty years ago. Then things slowly started to change.’

In 1961 English geneticist Mary Frances Lyon found that, even though women have two X chromosomes, one is randomly inactivated in every cell. In other words, only one of them shows up for work. Women are therefore a genetic mosaic in which some cells have genes from one X chromosome, and other cells have genes from the other. Researchers have more recently discovered that some of the genes on the second X chromosome aren’t actually inactivated at all. Christine Disteche, a professor of pathology at the University of Washington, Seattle, and one of the world’s leading researchers on X inactivation, describes them as ‘little islands of escape’. In 2009 researchers at Penn State College of Medicine totted up these un-inactivated genes to discover that they comprise 15 per cent of genes on the second X. ‘We are now looking at huge datasets on gene expression between males and females, in humans and mice, to really try to see what is the extent of these differences,’ says Disteche.

‘Finding out that one of the two is not completely inactivated, it leads to speculation about lots of interesting aspects of life for women. It may be the reason we live longer,’ suggests Oertelt-Prigione.

The problem for all researchers in this area is that it’s not easy to distil the impact of the X chromosome from all the other factors that can cause a person to get sick or die. Most diseases don’t appear to be linked to one or even a few genes, in the way that X-linked genetic disorders such as haemophilia and muscular dystrophy are. The things that kill many of us, such as cardiovascular disease, are more complicated than that. Could genes from a second X chromosome have consequences for how the heart works, for instance?

To answer this question, Arthur Arnold and his team have used a special kind of laboratory animal, one with absolutely no difference between its males and females except for the number of X chromosomes they have. In nature, these creatures don’t exist. But by using genetic modification, scientists can come close to building them. Since sex hormones have the most obvious impact on male and female bodies before birth (without androgens a male wouldn’t develop male gonads, for instance), researchers have created laboratory mice for Arnold that don’t produce these hormones. The resulting mice have XY chromosomes, like a male, but also ovaries, like a female. This has allowed Arnold to compare genetically altered XY female mice to normal XX female mice. The only difference between them should be in their chromosomes. If their health differs, it’s purely because of the effects of their genes.

The results have indeed shown a link between the number of X chromosomes a mouse has and its health. Arnold describes ‘three dramatic cases’. When he and his team looked at body weight, they found that mice get fat if you remove their gonads. But animals with two X chromosomes get a lot fatter than those with just one. This mirrors something we see in human adults – women tend to have a higher percentage of fat mass in their bodies than men. ‘A second example is that if we give the mouse a heart attack, the animals with two X chromosomes do worse than the animals with one X chromosome,’ says Arnold. ‘And the third example in the mouse model is with multiple sclerosis, where we induced a multiple sclerosis-like disease in the mouse, and the animals that are XX do worse than the animals that are XY.’ Multiple sclerosis in humans, being an autoimmune disease, affects more women than men.

The take-home message from this research is that many of the sex differences we see in health are rooted deep down in genetics. ‘The study of mouse models has provided convincing evidence that cells with two X chromosomes are intrinsically different from those with one X chromosome. Sex differences caused by the number of X chromosomes can have a profound effect on disease,’ Arnold and his colleagues wrote in their paper about the experiment, published in 2016 in the journal Philosophical Transactions of the Royal Society of London Series B.

But not everyone is convinced. Some are dubious as to whether rodents can provide quite as much insight as Arnold believes they can. ‘Personally, I’m not a mouse fan,’ says Sabine Oertelt-Prigione. ‘I don’t know how translatable findings in mice are to humans … I think they have given us a lot of information, but I just wonder at this point how far we should pursue that.’

Other criticisms go further. In her 2013 book Sex Itself: The Search for Male and Female in the Human Genome, Harvard University professor of the social sciences Sarah Richardson questions the idea that every cell in the body is intrinsically different depending on someone’s sex, and that this leads to the gaps we see between women and men. ‘It is a widely shared consensus among social scientists that genomics is transforming social relations,’ she writes. ‘The same may be said of genetic research on sex and gender.’ Arthur Arnold, for instance, describes the effect of sex-biasing factors in our genes as a ‘sexome’ (like the genome, but for sex difference). ‘You can think of the cell as this kind of big network,’ he tells me. ‘Males and females are different because they have different levels of sex-biasing factors, and they pull on the network at various points.’ This idea suggests that even though the sex chromosomes are only one of the twenty-three pairs of chromosomes we have, their effects are wide-ranging.

Richardson warns against this focus on genetics as an umbrella explanation for sex difference because of how it blurs away the effects of society and culture, as well as other biological factors. Age, weight and race, for example, are known to have a huge impact on health. Hormones are important too. She notes that the body of genetic evidence when it comes to sex differences paints an overwhelming picture of similarity. Indeed, Arnold himself admits to me that his idea of the sexome is ‘more of an evocative phrase’ than a solid theory backed up by research.

The debate around just how deep the dividing line is between women and men continues to rage inside the scientific community. It has been fuelled most recently by anger over exactly the opposite problem: the habit in medical research of leaving women out of tests for new drugs, because their bodies are thought to be so similar to men’s.

‘It’s much cheaper to study one sex.’

‘Let’s face it, everyone in the biomedical community has spent their lives studying one sex or the other. And it’s usually males,’ says Steven Austad. When it comes to the basic machinery of our bodies, scientists have often assumed that studying one sex is as good as studying the other.

‘I one time looked into the rodent literature on dietary restrictions,’ recounts Austad. ‘There are hundreds and hundreds of studies. And I found that there was only a handful that included both sexes. And to me that just typifies the fact that people seem to be willing to extrapolate from one sex and just assume that everything they find is going to be true in the other sex.’

In 2011 health researcher Annaliese Beery at the University of California, San Francisco, and biologist Irving Zucker at the University of California, Berkeley, published a study looking into sex biases in animal research in one sample year: 2009. Of the ten scientific fields they investigated, eight showed a male bias. In pharmacology, the study of medical drugs, the articles reporting only on males outnumbered those reporting only on females by five to one. In physiology, which explores how our bodies work, it was almost four to one.

It’s an issue that runs through other corners of science too. In research on the evolution of genitals (parts of the body we know for certain are different between the sexes), scientists have also leaned towards males. In 2014 biologists at Humboldt University in Berlin and Macquarie University in Sydney analysed more than three hundred papers published between 1989 and 2013 that covered the evolution of genitalia. They found that almost half looked only at the males of the species, while just 8 per cent looked only at females. One reporter, Elizabeth Gibney, described it as ‘the case of the missing vaginas’.

When it comes to health research, the issue is more complicated than simple bias. Until around 1990, it was common for medical trials to be carried out almost exclusively on men. There were some good reasons for this. ‘You don’t want to give the experimental drug to a pregnant woman, and you don’t want to give the experimental drug to a woman who doesn’t know she’s pregnant but actually is,’ says Arthur Arnold. The terrible legacy of women being given thalidomide for morning sickness in the 1950s proved to scientists how careful they need to be before giving drugs to expectant mothers. Thousands of children were born with disabilities before thalidomide was taken off the market.

‘You take women of reproductive age off the table for the experiment, which takes out a huge chunk of them,’ continues Arnold. A woman’s fluctuating hormone levels might also affect how she responds to a drug. Men’s hormone levels are more consistent. ‘It’s much cheaper to study one sex. So if you’re going to choose one sex, most people avoid females because they have these messy hormones … So people migrate to the study of males. In some disciplines it really is an embarrassing male bias.’

This tendency to focus on males, researchers now realise, may have harmed women’s health. ‘Although there were some reasons to avoid doing experiments on women, it had the unwanted effect of producing much more information about how to treat men than women,’ Arnold explains. A 2010 book on the progress in tackling women’s health problems, co-written by the Committee on Women’s Health Research, which advises the National Institutes of Health (NIH) in the USA, notes that autoimmune diseases – which affect far more women than men – remain less well understood than some other conditions: ‘Despite their prevalence and morbidity, little progress has been made toward a better understanding of those conditions, identifying risk factors, or developing a cure.’

Another problem is that women may respond differently from men to certain drugs. Medical researchers in the mid-twentieth century often assumed this wasn’t a problem. ‘There was a notion that women were more like little men. There was a notion that if this treatment works in men, it will work on women,’ says Janine Clayton, director of the Office of Research on Women’s Health at the NIH in Washington, DC, which funds the vast majority of American health research.

We now know this isn’t necessarily true. In 2001, New Zealand-based dermatologist Marius Rademaker estimated that women are around one and a half times as likely to develop an adverse reaction to a drug as men. In 2000 the United States Government Accountability Office looked at the ten prescription drugs withdrawn from the market since 1997 by the US Food and Drug Administration. Studying reported cases of adverse effects, it found that eight posed greater health risks to women than to men. The withdrawn drugs included two appetite suppressants, two antihistamines and one for diabetes. Four of these were simply given to many more women than men, but the other four showed this effect even when men took them in more equal numbers.

‘You have to be concerned that there were serious enough side effects, not just a minor side effect but a serious enough adverse effect that resulted in the drug being withdrawn. I think that tells us that we’re only just seeing the tip of the iceberg of this issue,’ Janine Clayton tells me. This has become a huge concern for women’s health activists, particularly in the United States, and has been one of the mandates of the Office of Research on Women’s Health since 1990.

‘As clinicians, we know very well that diseases show up differently in men and women. Every day, men and women present to the emergency room with different symptoms with the same condition,’ says Clayton. ‘So heart attacks, for example, have different symptoms. Our research has shown that women who are going to have a myocardial infarction [heart attack] are more likely to have symptoms like insomnia, increasing fatigue, pain anywhere in the head all the way down to the chest, the weeks before they have a heart attack. Whereas men are less likely to have those symptoms, and are more likely to present with the classic crushing chest pain.’ Given differences like these, she believes that excluding them from drug trials for so many years must have affected women’s health. ‘It’s certainly a real possibility that the reason there are more adverse events in women than in men is because the whole process of drug discovery is tremendously biased towards the male,’ agrees Kathryn Sandberg.

Again, though, this line of thinking risks drawing divisions between women and men, when the picture of disease is far more complicated. While there’s a clear benefit to better understanding women’s bodies and having drugs that suit both sexes, the emphasis on sex difference starts to make it seem as though women’s bodies are from Venus and men’s are from Mars. ‘Given the well-documented history of methodological problems with sex difference research, as well as harmful abuses of sex difference claims by those who would limit women’s opportunities, it is remarkable to find women’s health activists promoting, with little qualification, sex-based biology’s expansive picture of sex differences,’ writes Sarah Richardson in Sex Itself.

But does it have to be one or the other? Is the only alternative to women being thought of as ‘little men’ to have them treated as an entirely different kind of patient? As more detailed research is done, it’s becoming clear that seeing some variation between women and men when it comes to health and survival doesn’t mean we should ditch the notion that our bodies are in fact similar in most ways.

This is a cautionary tale of two drugs.

The first is digoxin, which has long been used to treat heart failure. In 2002 researchers at the Yale University School of Medicine decided to take a look at the data around the drug, analysing its effects by sex. Between 1991 and 1996, other researchers had carried out randomised trials on heart patients using digoxin. They found that it didn’t affect how long a patient lived, but it did on average reduce their risk of hospitalisation. The Yale researchers noted that the drug was tested on around four times as many men as women, and that they didn’t respond identically. A slightly higher proportion of women taking digoxin died earlier than those taking a placebo. For men, the gaps between those taking the drug and the placebo group were much smaller. The sex difference, the Yale team concluded, ‘would have been subsumed by the effect of digoxin therapy among men’.

But science never stands still. The Yale result later turned out not to be what it seemed. More recent studies, including one with a much larger sample group published in the British Medical Journal in 2012, have suggested that in fact there isn’t a substantially increased risk of death for women from digoxin use at all.

The second example is the insomnia drug zolpidem, commonly sold in the United States under the brand name Ambien. Sleeplessness is big business for pharmaceutical companies. Around sixty million sleeping pills were prescribed in the US in 2011, up from forty-seven million just five years earlier, according to data collected by the healthcare intelligence company IMS Health. And Ambien is among the most popular. Its side effects, however, include severe allergic reactions, memory loss and the possibility of it becoming habit-forming. The effects of zolpidem can also lead to drowsiness the following day, which can make it dangerous to drive. Long after the drug was approved for market, research emerged that women given the same dose as men were more likely to suffer this morning drowsiness. Eight hours after taking zolpidem, 15 per cent of women but only 3 per cent of men had enough of the drug in their system to increase their risk of a traffic accident.

At the start of 2013 the US Food and Drug Administration took the landmark decision to lower the recommended starting dose of Ambien, halving it for women. ‘Zolpidem is kind of like a signal case,’ says Arthur Arnold.

Again though, just as with digoxin, the finding needed to be unpicked a little further. In 2014, additional research exploring the effects of zolpidem, carried out by scientists at Tufts University School of Medicine in Boston, suggested that its lingering effect in women may be mostly down to the fact that they have a lower average body weight than men, which means the drug clears from their systems more slowly.

Digoxin and zolpidem highlight the pitfalls of including sex as a variable in medical research. Besides a lower average body weight and height, women also have a higher percentage of body fat than men on average. And they generally take longer to pass food through their bowels. Both are things that might affect how drugs behave in their bodies. But they are also factors on which men and women overlap. There are many women who are heavier than the average man, for instance. It’s not always the case that the sexes belong in two separate categories.

What also counts is the experience of being a woman, socially, culturally and environmentally. ‘Both sex and gender are important factors for health,’ says Janine Clayton. Ideally, then, people should be treated according to the spectrum of factors that set them apart. Not just sex, but social difference, culture, income, age and other considerations. As Sarah Richardson has written, ‘a female rat – not to mention a cell line – is not an embodied woman living in a richly textured social world’.

The problem is that ‘medicine is very binary. Either you get the drug or you don’t. Either you do this or you do that,’ says Sabine Oertelt-Prigione. ‘So the only step, I believe, is to incorporate the notion that there is actually not one neutral body, but at least two. I believe it’s just another way of looking at things. In medicine, just having a way to change paradigms and look at things differently can open up whole arrays of possibilities. It could be looking at sex differences, but there are many other things that could help to make healthcare more inclusive in the end.’

‘What are we trying to do? We’re trying to improve human health, right?’ says Kathryn Sandberg. ‘So if we see a disease is more prevalent or more aggressive in men than women, or vice versa, we can learn a lot about that disease by studying why one sex is more susceptible while the other is more resilient. And this information can lead to new treatments that benefit all of us.’ Understanding why women tend to live longer could help men live longer. Including pregnant women in research may open up the cabinet of drugs that doctors can’t currently prescribe because their effects on foetuses are uncertain. Medical dosages might be affected by a better understanding of how a woman’s body responds across her menstrual cycle.

At the moment at least, the verdict of politicians and scientists seems to be that including sex as a variable when carrying out medical research can improve overall health. In 1993 the US Congress introduced the National Institutes of Health Revitalization Act, which includes a general requirement for all NIH-funded clinical studies to include women as test subjects, unless they have a good reason not to. By 2014, according to a report in Nature by Janine Clayton, just over half of clinical-research participants funded by the NIH were women.

Since the start of 2016 the law in the USA has been broadened to include females in vertebrate animal and tissue experiments. The European Union now also requires the researchers it funds to consider gender as part of their work.

For women’s health campaigners and researchers like Janine Clayton and Sabine Oertelt-Prigione, this is a victory. To have females equally represented in research is something they’ve spent decades fighting for. Male bias, where it exists, is being swept away. Women are being taken into account. Maybe we will finally understand just what it is that makes women on average better survivors, and why men seem to report less sickness.

But as science enters this new era, scientists need to be careful. Research into sex differences has an ugly and dangerous history. As the examples of digoxin and zolpidem prove, it’s still prone to errors and over-speculation. While it can improve understanding, it also has the potential to damage the way we see women, and to drive the sexes further apart. The work being done into genetic sex differences by people like Arthur Arnold doesn’t just impact medicine, but also how we see ourselves.

Once we start to assume that women have fundamentally different bodies from men, this quickly raises the question of how far the gaps stretch. Do sex chromosomes affect not just our health, but all aspects of our bodies and minds, for example? If every cell is affected by sex, does that include brain cells? Do oestrogen and progesterone not just prepare a women for pregnancy and boost her immunity, but also creep into her skull, affecting how she thinks and behaves? And does this mean that gender stereotypes, such as baby girls preferring dolls and the colour pink, are in fact rooted in biology?

Before we know it we land on one of the most controversial questions in science: are we born not just physically different, but thinking differently too?